The Incidence of Deep Vein Thrombosis in Breast Cancer Patients Receiving Outpatient Cancer Therapy in Iran.

Background: Venous thromboembolism (VTE) is one of the main causes of mortality in patients with cancer. This study was conducted to assess the incidence of deep vein thrombosis (DVT) in breast cancer patients receiving outpatient cancer therapy. Materials and Methods: This multi-center prospective cohort study was conducted on patients with breast cancer, initiating an outpatient chemotherapy regimen in five medical centers in Iran. Eligible patients were enrolled in the study consecutively between January 2013 and January 2015. The primary outcome was lower extremity DVT based on duplex/doppler ultrasonography two months after the first course of chemotherapy (visit 2) and after the end of the course (visit 3). All patients were followed-up from the onset of chemotherapy until the first occurrence of lower extremity DVT, death, or the end of the course. Results: A total of 427 eligible breast cancer patients were recruited in the study, 403 of whom attended at least one follow-up visit. The mean (SD) duration of follow-up was 4 (1.3) months. During the follow-up, only one patient showed DVT on duplex/doppler ultrasonography in visit 2. Therefore, the two-month and overall cumulative incidence risk of DVT was 0.25% (95% CI: 0.00–0.74%). However, the mean D-dimer level showed no significant change (P>0.05). Conclusion: Our findings showed the low risk of DVT in breast cancer patients receiving outpatient cancer therapy.

INTRODUCTION fold increased risk of VTE, compared to women without cancer in the same age group (9). Given the high incidence of breast cancer among women worldwide (8), even a small increase in the occurrence of VTE in these patients can have a substantial impact on public health and medical resources (9,10).
To the best of our knowledge, only one recently published study has assessed the incidence of deep venous thrombosis (DVT) in outpatients with breast cancer (11).
Therefore, the purpose of the present study was to assess the incidence of lower extremity DVT in breast cancer outpatients receiving outpatient cancer therapy.

Study design and participants
This prospective multi-center cohort study was conducted on patients with breast cancer, who were scheduled to start outpatient systemic treatment in five medical centers of Iran. The study was performed in four hospitals and one private clinic, including Omid Hospital (Urmia), Namazi Hospital (Shiraz), Imam Hossein Hospital (Tehran), Imam Reza Hospital (Mashhad), and Dr. Najafi Private Clinic (Tehran). Breast cancer patients referred to these centers were included if they met the following criteria: 1) written informed consent; and 2) plan for initiation of outpatient cancer therapy within one month.
On the other hand, the exclusion criteria were as follows: 1) a history of hospitalization and/or surgery within two weeks before the study; 2) hospitalization for more than three days during the study; 3) a documented acute DVT at This study was reviewed and approved by the Ethics Committee of Masih Daneshvari Hospital in Tehran, Iran.
In accordance with the ethics committee requirements and Declaration of Helsinki by the World Medical Association (WMA), all patients received the necessary information about the study before they were asked to sign a consent form if they were willing to participate. Patients could withdraw consent at any time throughout the study for any reason. All patients' data remained anonymous in the study.

Data collection
In baseline and follow-up visits, all necessary data were collected from the patients' medical files and records and transferred into a case report form (CRF), which was developed a priori by trained nurses. The recorded data on CRFs were submitted to a central coordinating center. All collected data are listed below: In the first visit (baseline):

Data quality control
The quality of the recorded data was controlled by comparing the collected data with the medical records of patients of all included centers after each visit. In addition, the plausibility and completeness of the key transferred data were checked randomly and regularly by data managers at the coordinating center. The centers were contacted in the event of any discrepancy or missing value to ask for modification or verification of the data. The study sites were visited regularly by clinical examiners to check for informed consents and key data.

Variable measurements
BMI was calculated based on the measured height and weight (kg/m 2 ) in the baseline visit and was classified into

Outcome measurements
The main outcome was the incidence of DVT during chemotherapy in breast cancer outpatients. In each followup visit, all patients were screened for DVT by performing lower extremity Doppler ultrasonography and assessing D-dimer regardless of whether the patient was symptomatic or not. DVT was defined using the validated ICD-9-CM diagnostic codes for thrombophlebitis and venous thrombosis of the lower extremity. It was diagnosed based on the clinical symptoms or physical signs and confirmed using the duplex/doppler ultrasonography criteria for DVT by the treating physician.

Statistical methods and data analysis
The baseline characteristics of the patients were summarized and presented with descriptive statistics, and inter-cohort comparisons were performed. Categorical variables were reported as percentage (absolute frequency) and compared using two-sided Chi-square tests.
Continuous variables were reported as mean (standard deviation) and compared using student's t-tests or repeated measurement tests. P-value less than 0.05 was considered statistically significant. The cumulative incidence risk and 95% confidence intervals were also calculated. All statistical analyses were performed using SAS version 19.0 (SAS Institute Inc., Cary, NC).

D-dimer measurements during follow-ups
In patients who attended at least one follow-up visit,

DISCUSSION
In this prospective cohort study, the incidence of clinical DVT in breast cancer patients receiving outpatient chemotherapy was approximately 0.25%, which was lower than expected. In line with our findings, some other studies have also reported the low incidence risk of VTE (0.18-0.28%) even after one or two months of surgery in patients with breast cancer (2,14). Due to the low incidence rate of the outcome (DVT), we were unable to assess the effect of risk factors.
Generally, previous studies have reported different risks of VTE events in patients with breast cancer (Table 4). This is probably due to differences in the baseline and clinical characteristics of the patients, treatment-related factors, prophylactic interventions, diagnostic approaches, and/or duration of follow-up (15). Therefore, the risk of VTE events has not been precisely determined in breast cancer patients. Furthermore, a short follow-up may lead to an underestimation of the exact incidence. However, evidence suggests that the risk of VTE is the highest in the first three months after diagnosis (15). In addition, Walker et al. (18) found that in breast cancer patients, the effect of chemotherapy on the incidence of VTE is probably limited to the period of active treatment. Most of our patients were followed-up to the end of the last chemotherapy course.
Other possible explanations for the low incidence of DVT  In general, development of VTE in cancer patients is known to be associated with an increase in morbidity, mortality, and medical costs (15). Although systemic VTE prophylaxis is not routinely recommended in breast cancer patients due to the relatively low incidence of VTE and the increased risk of bleeding in this group (31,32), high-risk patients would potentially benefit from early detection of the problem (18,19). However, breast cancer patients are all advised to use mechanical anti-embolism devices along with early ambulation in the postoperative period (29). In addition, the only patient who was categorized as high-risk based on the Khorana VTE-RS at baseline, missed both follow-ups, and this missing data could have affected our results.

CONCLUSION
Based on our finding, the incidence of clinical DVT in breast cancer patients receiving outpatient chemotherapy is low. Therefore, routine use of thromboprophylaxis in these patients is not recommended.